Genetics of Chronic Pancreatitis – New Aspects?

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Genetics of Chronic Pancreatitis – New Aspects?

Journal Title: Postępy Nauk Medycznych - Year 2011, Vol 24, Issue 3

Abstract

Fifteen years ago the discovery of a mutation of the cationic trypsinogen gene (PRSS1) in patients with hereditary chronic pancreatitis supported Hans Chiari’s theory that chronic pancreatitis is the result of autodigestion of the pancreas and depicted the fundament for further research in this field. A genetic basis for chronic pancreatitis had to be assumed in a pedigree described by Comfort and Steinberg already in 1952 it needed additional 44 years to identify this first genetic association. Thereafter, research had its focus on proteases and anti-proteases that are assembled in the digestive enzyme cascade, an approach that identified serine protease inhibitor, Kazal type 1 (SPINK1) as another pancreatitis gene. Aside the digestive enzyme cascade, the cystic fibrosis transmembrane conductance regulator gene (CFTR) that is responsible for Cystic Fibrosis, was investigated by two groups and both found an enrichment of CFTR variants in patients with chronic pancreatitis. Support for this investigation came from Cystic Fibrosis, where 1-2% of patients suffer from chronic pancreatitis. New aspects in the field of genetics in chronic pancreatitis emerged in the last five years. A variant of anionic trypsinogen (PRSS2) was found to be overrepresented in controls and protects against chronic pancreatitis. Additionally, variants of the calcium sensing receptor (CASR) seem to influence the pathogenesis of chronic pancreatitis in SPINK1 p.N34S carriers. Triplication and duplication of the trypsinogen locus represents a completely new disease causing mechanism that predisposes to chronic pancreatitis by a so-called gene dosage effect. Identification of chymotrypsin C (CTRC) as the enigmatic Enzyme Y described by Rinderknecht over 20 years ago displayed another reasonable candidate gene. Investigations of CTRC found low penetrance loss of function variants that diminish secretion and/or activity of CTRC and thereby contribute to the development of the disease. Taken together recent data further support the importance of a balanced digestive enzyme cascade in that trypsin captures a key role. Further research in this field will yield additional associated genes by hypothesis-driven and hypothesis free approaches.

Authors and Affiliations

Jonas Rosendahl, Joachim Mössner

Keywords

Genetics chronic pancreatitis PRSS1 PRSS2 SPINK1 CFTR CTRC CASR

EP ID EP54129
DOI -
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